Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues

J Enzyme Inhib Med Chem. 2018 Dec;33(1):794-803. doi: 10.1080/14756366.2018.1458030.


Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with Ki values of 11.12 ± 2.88 and 29.86 ± 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of β-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity.

Keywords: X-ray Crystallography; acetylcholinesterase; donepezil analogues; inhibition kinetics; β-secretase-1.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Crystallography, X-Ray
  • Donepezil
  • Dose-Response Relationship, Drug
  • Indans / chemistry
  • Indans / pharmacology*
  • Kinetics
  • Molecular Docking Simulation
  • Molecular Structure
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship
  • Torpedo


  • Cholinesterase Inhibitors
  • Indans
  • Piperidines
  • Donepezil
  • Acetylcholinesterase

Grants and funding

Nutramed SCaRL, actuator of the Project PON03PE_00078_1 and PON03PE_00078_1/F1, is acknowledged for the financial support.